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Ibritumomab Tiuxetan (Zevalin ™ ) Radioimmunotherapy of Non-Hodgkin’s Lymphoma

Ibritumomab Tiuxetan (Zevalin ™ ) Radioimmunotherapy of Non-Hodgkin’s Lymphoma. Oncology Drug Advisory Committee Meeting September 11, 2001. ODAC Presentation 1. Presentation Agenda. Opening remarks Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs*

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Ibritumomab Tiuxetan (Zevalin ™ ) Radioimmunotherapy of Non-Hodgkin’s Lymphoma

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  1. Ibritumomab Tiuxetan (Zevalin™) Radioimmunotherapy of Non-Hodgkin’s Lymphoma Oncology Drug Advisory Committee MeetingSeptember 11, 2001 ODAC Presentation 1

  2. Presentation Agenda • Opening remarks • Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs* • Scientific and medical summary of Zevalin • Christine A. White, M.D. - Vice President, Medical Affairs* • Discussion • Christine A. White, M.D. - Vice President, Medical Affairs* • Pratik Multani, M.D. - Director, Medical Affairs* • Bryan Leigh, M.D. - Director, Oncology* *IDEC Pharmaceuticals, San Diego, CA

  3. Zevalin™ (ibritumomab tiuxetan):Proposed Indication • Treatment of patients with relapsed or refractory, low-grade, follicular, or CD20+ transformed B-cell non-Hodgkin’s lymphoma (NHL) and treatment of patients with rituximab-refractory follicular NHL ODAC Presentation 3

  4. Non-Hodgkin’s Lymphoma • Most NHL are of B cell origin and express CD20 • Ranks 5th in cancer incidence and mortality • Incidence: 54,900/year • Prevalence: 300,000 cases • 65% low-grade or follicular • Transformation increases over time • Median age at diagnosis: 60 years • Median survival • Low-grade or follicular: 6.2 years • From transformation: 7 to 22 months

  5. Zevalin Regimen Therapeutic dose Imaging dose Rituximab (250 mg/m2) Rituximab (250 mg/m2) Followed by 90Y Zevalin (0.4 or 0.3 mCi/kg;max dose 32 mCi) Followed by 111In Zevalin 5 mCi (1.6 mg) Day 1 2 3 4 5 6 7 8 Scans 90 - 120 hours(optional) 2 - 24 hours 48 - 72 hours

  6. Single Point Distribution System IDEC 111 Indium Isotope Supplier 90 Yttrium Isotope Supplier Distributor 111 In Kit 90Y Kit NUCLEAR PHARMACY

  7. Clinical Basis for BLA ODAC Presentation 7

  8. FDA Agreements • Phase III Randomized Trial (106-04) • Primary endpoint: ORR • Designed with 80% power to detect a difference in ORR • TTP to be clinically equivalent to control (within 1.5 months) • Phase III Rituximab-Refractory Trial (106-06) • Fast Track: June 5, 2000 ODAC Presentation 8

  9. Zevalin™ (ibritumomab tiuxetan):Summary • Clinically significant activity • Acceptable toxicity Zevalin represents a clinically meaningful advance in therapy ODAC Presentation 9

  10. IDEC Investigators • Thomas Witzig, M.D.Mayo Clinic • Sandra Horning, M.D.Stanford UniversityECOG Lymphoma Chair • Myron Czuczman, M.D.Roswell Park Cancer Center • Gregory A. Wiseman, M.D.Mayo Clinic • Andrew Raubitschek, M.D.City of Hope • Albert LoBuglio, M.D.University of Alabama, Birmingham ODAC Presentation 10

  11. IDEC Investigators (cont.) • Leo Gordon, M.D.Northwestern University • LEXCORDonald Klippenstein, M.D.Roswell Park Cancer Center • DosimetryMichael Stabin, Ph.D., C.H.P.Oak Ridge Institute for Science and Education • Larry Cripe, M.D.Indiana University Cancer Center • RadioincorporationMichael Zimmer, Ph.D.Northwestern University ODAC Presentation 11

  12. Presentation Agenda • Opening remarks • Leslie L. Shelly, Ph.D. - Associate Director, Regulatory Affairs* • Scientific and medical summary of Zevalin • Christine A. White, M.D. - Vice President, Medical Affairs* • Discussion • Christine A. White, M.D. - Vice President, Medical Affairs* • Pratik Multani, M.D. - Director, Medical Affairs* • Bryan Leigh, M.D. - Director, Oncology* *IDEC Pharmaceuticals, San Diego, CA

  13. Ibritumomab Tiuxetan (Zevalin™) Radioimmunotherapy of Non-Hodgkin’s Lymphoma Christine A. White, M.D. Vice President, Medical Affairs IDEC Pharmaceuticals Corporation Oncology Drug Advisory Committee MeetingSeptember 11, 2001 ODAC Presentation 13

  14. Presentation Outline • Background • Phase I/II conclusions • Imaging and dosimetry • Phase III randomized trial • Phase III rituximab-refractory trial • Efficacy in transformed/nonfollicular low-grade • Integrated safety summary • Conclusions ODAC Presentation 14

  15. Percent of responding patients in remission Response Rate and Duration Decrease with Successive Courses of Alkylator-Based Therapies 100 Response Rate (%) Rx 1 70 80 2 59 1st Rx 3 59 4 44 60 5 39 40 2nd Rx 3rd Rx 20 4th Rx 1 2 3 4 Years Source: Gallagher et al. J Clin Oncol 1986;4(10):1470-80 ODAC Presentation 15

  16. Treatment of Relapsed or Refractory LG/F/T NHL • Typically multiple cycles per course of therapy ODAC Presentation 16

  17. < 1 - 10% Toxicities of Commonly Used Regimens Treatment Agent Neutropenia Thrombocytopenia Infection • Grade 3 and 4 neurotoxicity in up to 10%; renal/hepatic toxicity in up to 21% Related Grade 4 (# of Studies) Grade 4 Grade 3 & 4 Deaths ICE (1) 13% 15% 14% NA ESHAP (1) 50% NA 30% 16% DHAP (1) 53% 39% 31% 17% CHOP (6) 16 - 39% 2 - 12% 3 - 33% Fludarabine (5) 5 - 59% 0 - 3% 1 - 14% 3 - 5% Cladribine (5) 13 - 36% 4 - 13% 8 - 40% 3 - 23% ODAC Presentation 17

  18. Treatment of Relapsed or Refractory LG/F/T NHL • No conventional chemotherapy regimen is curative • No regimen has been shown to be superior with regard to survival • Patients need additional treatment options • In the absence of cure or survival benefit, treatments that induce remission and prolong time off therapy are valuable ODAC Presentation 18

  19. Rationale for Radioimmunotherapy in NHL • NHL is inherently sensitive to radiation • RT can be curative in limited stage NHL but can not be applied to advanced stage disease • RIT antibodies target radiation to tumor • RIT can kill both bound and neighboring tumor cells, overcoming the problem of access in bulky or poorly vascularized tumors

  20. Critical Factors for Successful RIT • Target antigen • Antibody selectivity • Choice of isotope • Stability of antibody-isotope linkage

  21. Zevalin (ibritumomab tiuxetan) • Ibritumomab (murine parent of rituximab) • Binds CD20 • Tiuxetan • Stable retention of 90Y CD20 antigen 90Y Zevalin B cell • CD20 antigen • Expressed only onB-lineage cells • Important for cell cycle initiation and differentiation • Does not shed or modulate Ibritumomab Tiuxetan 90Y ODAC Presentation 21

  22. Choice of Isotope 90Y 90Y 90Y 90Y 90Y 90Y ODAC Presentation 22

  23. Presentation Outline • Background • Phase I/II conclusions • Imaging and dosimetry • Phase III randomized trial • Phase III rituximab-refractory trial • Efficacy in transformed/nonfollicular low-grade • Integrated safety summary • Conclusions ODAC Presentation 23

  24. Zevalin Phase I and I/II Conclusions • Unlabeled pretreatment rituximab improves Zevalin biodistribution • MTD: 0.4 mCi/kg (0.3 mCi/kg for patients with mild thrombocytopenia), max 32 mCi • Toxicity primarily hematologic and reversible • Correlated with mCi/kg dose • Clinical variables (baseline platelets, % marrow NHL involvement) more predictive of toxicity than dosimetry • Clinical parameters adequate for dosing

  25. Zevalin Phase I/II Study (N = 51) • ORR: 82% in low-grade NHL 42% in intermediate-grade NHL • Median TTP (responders): • 0.4 mCi/kg: 15.4 months • 0.4 mCi/kg CR pts: 28.3 - 37.2+ months

  26. Presentation Outline • Background • Phase I/II conclusions • Imaging and dosimetry • Phase III randomized trial • Phase III rituximab-refractory trial • Efficacy in transformed/nonfollicular low-grade • Integrated safety summary • Conclusions ODAC Presentation 26

  27. 111In-Labeled Zevalin Imaging 66 hours 4 hours 139 hours Abdominal SPECT Abdominal CT ODAC Presentation 27

  28. Imaging and Dosimetry • Tumors imaged in all LG/F/T patients • Radiation absorbed dose to normal organs acceptable in all patients • Minimal urinary excretion, 7% over 7 days • No correlation between hematologic toxicity and dosimetry or PK parameters

  29. Spleen* 1053 Testes† 950 Liver* 520 Lower Large Bowel 326 Heart Wall 292 Lungs 220 Upper Large Bowel 196 Red Marrow 143 Small Bowel 129 Thyroid 35 Other Organs‡ 35 Kidneys 13 Total Body 58 Median 90Y Radiation Absorbed Dose Tumor 1480 0 200 400 600 800 1000 1200 1400 1600 2000 cGy *All spleen and liver doses were adjusted for organ mass †10 men for sex-specific organs‡Adrenals, brain, breasts, gallbladder wall, muscle, pancreas, skin, thymus, stomach ODAC Presentation 29

  30. Presentation Outline • Background • Phase I/II conclusions • Imaging and dosimetry • Phase III randomized trial • Phase III rituximab-refractory trial • Efficacy in transformed/nonfollicular low-grade • Integrated safety summary • Conclusions ODAC Presentation 30

  31. Phase III Randomized Trial RituximabRefractoryTrial (N = 54) Zevalin Rituximab (N = 73) (N = 70) 60 57 54 0.9 1 0.9 75% 83% 100% 12% 11% 0% 12% 6% 0% 89% 91% 91% 43% 34% 32% Representative Population • Similar to 1850 patients from 7 literature reports *Dana et al., 1993; Johnson et al., 1995; Bastion et al., 1997; Armitage and Weisenburger, 1998; Lopéz-Guillermo et al., 1998; McLaughlin et al., 1998; Rosenberg et al., 1982 ODAC Presentation 31

  32. Phase III Randomized Controlled Study Mayo Clinic Northwestern UnivMD AndersonUCLARoswell ParkHarvard/Beth IsraelCleveland ClinicWashington Univ Jewish Hospital Kenwood, OHFox Chase Cancer Center Mountain States Tumor InstituteUniv of FloridaGreenville Hospital, SCUniv of Alabama Henry Ford Cancer CenterJohns Hopkins UnivKansas UnivSutter Cancer CenterSt. Vincent’s HospitalGreenbaum Cancer Center, MDCity of HopeSharp/Sidney Kimmel Cancer CenterNYUGeorgetown UnivWestern Penn Cancer InstituteNew York HospitalKaiser Permanente, CA ODAC Presentation 32

  33. Study Design Zevalin regimenDay 1: Rituximab (250 mg/m2) 111In Zevalin (5 mCi) Day 7, 8, or 9: Rituximab (250 mg/m2) 90Y Zevalin (0.4 mCi/kg; max 32 mCi) RANDO MIZATION STRATIFIED by histology: IWF A, follicular, ortransformed Rituximab control(375 mg/m2 weekly x 4)

  34. Prospectively-Defined Efficacy Endpoints • Primary: ORR • Designed with 80% power to detect a difference of 25% in ORR (alpha = 0.05) • Determined by independent LEXCOR panel blinded to treatment arm and investigator-assessed response • Secondary: DR, TTP, time to next therapy, CR, CCR, PR, QOL

  35. Enrollment Criteria • Inclusion • Bidimensionally measurable disease • <25% marrow involvement by biopsy • WHO performance status < 2 • ANC > 1,500/mm3, platelets > 150,000/mm3 • Exclusion • Prior myeloablative therapy or RIT • Prior radiation to > 25% of active marrow • Prior anti-CD20 therapy • Total bilirubin or creatinine > 2.0 mg/dL • ALC > 5,000/mm3

  36. Demographics/Disease Status • Well-balanced • No statistically significant differences in: • Age • Sex • Race • Stage • Histology • No. of prior regimens • Response to last therapy • Marrow involvement • Splenomegaly • Bulky disease • IPI risk group • Chemoresistance

  37. Demographics/Disease Status *Included SLL, MALT, lymphoplasmacytic, and monocytoid B ODAC Presentation 37

  38. Disease Status (cont.) *Resistance defined as no response or TTP < 6 months ODAC Presentation 38

  39. CR CCR PR Response AssessmentProtocol-Defined Response Criteria 100 Response p-value 90 ORR 0.002 73% 80 CR 0.326 70 18% 60 3% 47% 50 Response Rate (%) 11% 40 4% 52% 30 31% 20 10 0 Zevalin Rituximab (N = 70) (N = 73) ODAC Presentation 39

  40. Response by Histology Protocol-Defined Response Criteria *p-values generated by Fisher’s exact two-tailed test†Included SLL, MALT, lymphoplasmacytic, and monocytoid B ODAC Presentation 40

  41. Response in Chemoresistant Patients Protocol-Defined Response Criteria Resistant to last chemotherapy; resistance defined as no response or TTP < 6 months *p-value generated by Fisher’s exact two-tailed test ODAC Presentation 41

  42. Response by Tumor BulkProtocol-Defined Response Criteria ODAC Presentation 42

  43. CR CRu PR Response AssessmentInternational Workshop Response Criteria 100 Response p-value 90 80% ORR 0.002 80 CR 0.040 70 30% 56% 60 16% 50 Response Rate (%) 4% 40 4% 30 45% 36% 20 10 0 Zevalin Rituximab (N = 73) (N = 70) ODAC Presentation 43

  44. Duration of Response and TTP (months) Based on Kaplan-Meier estimationMedian observation time: 22 months ODAC Presentation 44

  45. Duration of Response by Histology *p-value generated by Log-rank test ODAC Presentation 45

  46. 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 100 C 90 TTP: All Patients 80 C 70 60 C Progression Free (%) C C C 50 C C C C C C C C C C C C 40 C C C C C C C C C Zevalin (N = 73) C C C C 30 C C C C C C C C C C C C C C C C 20 p = 0.173Log-rank test Rituximab (N = 70) 10 0 Kaplan-Meier AnalysisC = censored Months ODAC Presentation 46

  47. Time to Next Therapy All Patients 100 90 C 80 C 70 C C C C C C C C C C Zevalin (N = 73) 60 C C C C C C C C C C C C C Patients Without Therapy (%) C C C C C C C C C C C C C C C C C C C C C 50 C C C C C C C C C C C C C C C 40 C C C C C C C C C C C Rituximab (N = 70) 30 20 p = 0.084Log-rank test 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Kaplan-Meier AnalysisC = censored Months ODAC Presentation 47

  48. 100 90 80 70 60 50 40 30 20 10 0 TTP: Follicular Patients C C C C Progression Free (%) C C C C C C C C C C C C C C C C C Zevalin (N = 55) C C C C C C C C C C C C C C C C C C C Rituximab (N = 58) p = 0.062Log-rank test 0 3 9 12 15 21 24 30 6 18 27 33 36 Kaplan-Meier AnalysisC = censored Months ODAC Presentation 48

  49. 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time to Next TherapyFollicular Patients C C C Zevalin (N = 55) C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C Patients Without Therapy (%) C C C C C C C C C C C C C C C C C C C C C C C Rituximab (N = 58) p = 0.058Log-rank test Kaplan-Meier AnalysisC = censored Months ODAC Presentation 49

  50. 4 6 0 2 8 10 12 14 16 18 20 22 24 26 28 30 32 34 TTP: CR/CCR Patients 100 90 C C 80 Zevalin (N = 15) C C C C C C C C C 70 60 Progression Free (%) 50 C C C C Rituximab (N = 11) 40 30 20 p = 0.144Log-rank test 10 0 Kaplan-Meier AnalysisC = censored Months ODAC Presentation 50

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